Indomethacin [1-(4Chlorobenzoyl)-5-Methoxy-2-methyl-1H-indole-3-acetic acid] has superior anti-inflammatory, analgetic and antipyretic activities and is used in the form of capsules (Indocin®) for treatment of systemic inflammatory diseases (arthritis, muscle pain, tendonitis, etc.). Sodium salt of indomethacin may be injected intravenously or used for treatment of inflammatory conditions in the eye (Indocollyre®).
Indomethacin is practically insoluble in water. Solubility in water media improves with increased pH, but the produced solution of indomethacin salt is very unstable and degrades quickly, forming inactive compounds. Additionally, either indomethacin itself or sodium salt of indomethacin are highly irritating to mucous surfaces, causing stinging and burning sensations. Furthermore, extended use almost definitely produces ulceration.
In order to decrease such irritation, different derivatives of indomethacin have been explored. Multiple esters, amides, Mannich bases, and some other hydrolysable compounds were synthesized. Such modification usually leads to a decrease in ulcerogenicity and a decrease of local irritation, along with an increase in lipophilicity. In some cases, such modification has resulted in modified cyclooxygenase inhibition selectivity. For instance, indomethacin is a non-selective COX-1/COX-2 inhibitor, while many of its esters and other derivatives are described as selective COX-2 inhibitors. [U.S. Pat. No. 6,306,890 (“Esters Derived from Indolealkanols and Novel Amides Derived from Indolealkylamides that are Selective COX-2 Inhibitors”) and U.S. Pat. No. 6,762,182 (“Converting COX Inhibition Compounds that are not COX-2 Selective Inhibitors to Derivatives that are COX-2 Selective”), both to Kalgutkar et al.].
Different formulations of NSAIDs are used for the treatment of ophthalmic inflammation conditions. For example, Diclofenac sodium 0.1% (Voltaren® ophthalmic, Novartis), Bromfenac 0.09% (Xibrom®, ISTA/Senju Pharmaceuticals), Flurbiprofen sodium 0.03% (Ocufen®, Allergan, Bausch & Lomb), Indomethacin sodium 0.1% (Indocin® Ophthalmic, Merck, Indocollyre®, Chauvin) and 1.0% Indomethacin sodium (Indoptol®, Merck Sharp & Dohme), and Ketorolac tromethamine 0.5% (Acular®, Allergan) for ophthalmic applications are manufactured and marketed in many countries.
Due to the chemical structure and pharmacological properties of the NSAIDs, their application can cause local irritation, burning and itching sensations, and may delay wound healing. In some cases, use of NSAIDs may cause superficial punctate keratitis. [Salva P. et al., 1999; Scuderi B. et al., 2003; Mccarey B. et al., 1995; Stroobants A. et al., 2000; Diestelhorst M. et al., 1996].
New ophthalmic vehicles and delivery systems have been introduced in the last decade which improve the tolerability and increase the efficacy of ocular treatments. Bioadhesive inserts and gels, nanoparticles, nanocapsules, niosomes, liposomes, and microemulsions have been extensively investigated. [U.S. Pat. No. 5,496,811 (“Submicron Emulsions as Ocular Drug Delivery Vehicles”) to Aviv H. et al.; U.S. Pat. No. 5,364,632 (“Medicinal Emulsions”) to Benita S. and Levy M.; U.S. Pat. No. 5,171,566 (“Flurbiprofen Derivative Ophthalmic Preparation”); and U.S. Pat. No. 4,613,505 (“Ester of Flurbiprofen and Emulsion Containing the Same”), both to Mizushima Y. et al.].
Colloidal ophthalmic compositions show improved tolerance and better transport properties for incorporated drugs [Aggarwal D. et al., 2005; Mainardes R. et al., 2005; De T K et al., 2004; Calvo P. et al., 1996].
Menthol can improve the penetration of indomethacin across the skin in mixtures of indomethacin and menthol by increasing permeability of the skin. Menthol is irritative to the eye, however. Therefore, a mixture of menthol and indomethacin at concentrations high enough to show improved penetration of indomethacin would likely be too painful to the eye to permit a mixture of indomethacin and menthol to feasibly be used in an ophthalmic preparation.
Another disadvantage of indomethacin is that it is unstable at pH greater than 6.0. As such, indomethacin is unstable in the body pH of approximately 7.4.
Due to the limitations of current ophthalmic pharmaceutical compositions which comprise indomethacin or sodium salt of indomethacin, there is a need for an improved ophthalmic pharmaceutical composition of indomethacin that shows both enhanced stability, and lesser negative side effects.